Dr James Duce
Dr Duce is a Senior Research Fellow in the Institute of Molecular and Cellular Biology at the University of Leeds and is an associate member of the Astbury Centre. James obtained his PhD in neurobiology at the University of Wales College of Medicine in 2002, and immediately transitioned abroad to built his international experience by working as a research associate at Boston University School of Medicine with Prof. Carmela Abraham before moving to Australia and working with Profs. Ashley Bush and Colin Masters. After more than 10 years working overseas in some of the most recognized international groups, James recently returned to the UK and joined the University of Leeds at the beginning of 2012.
Research Areas: Neurobiology, metallomics, neurodegenerative disease
Advancing the basic understanding of β-amyloid precursor protein's role in neuroprotection.
β-amyloid precursor protein is a copper and zinc binding protein ubiquitously expressed as a full-length type 1 transmembrane protein, and processed into fragments, including the soluble species found in plasma (sAPP) and toxic β-amyloid peptide that accumulates in the ageing brain as well as neurodegenerative diseases including Alzheimer’s disease. Known to have neurotrophic properties, APP function was until recently largely unknown. But with a regulation of APP expression by iron regulatory protein (IRP) implying an interaction with iron status, our group has recently strengthened an iron relationship through the discovery of its ability to oxidize Fe2+ to a safer form of iron (Fe3+). This ferroxidase activity prevents oxidative stress caused by Fenton and Haber-Weiss chemistry and losses of ferroxidase activities may in part be responsible for pathological Fe2+ accumulation in neurodegenerative diseases. Aceruloplasminemia, a mutation of the multicopper ferroxidase ceruloplasmin (CP) leads to glial iron accumulation with dementia and we have recently discovered that APP ferroxidase activity is also diminished in Alzheimer’s disease. Multicopper ferroxidases (such as CP) and APP interact with the iron export protein; ferroportin and facilitate the removal of cytoplasmic iron via ferroportin’s translocation to the cell surface (see Figure). The loss of ferroxidase activity in disease is thought to lead to intracellular iron accumulation because of their ability to facilitate iron efflux. Iron-exporting ferroxidase expression is typically cell specific, within the brain, CP is expressed in glia and APP is presently the only known ferroxidase expressed in neurons.
Additional data by our group also indicates that APP has the ability to oxidase amines and is a significant factor in the clearance of catecholamine. It is notable that both APP and CP possess concomitant ferroxidase and amine oxidase activities. While the activity of both proteins is mediated by domains that are not structurally homologous and by different electrochemical reaction mechanisms, the similarities in activities are unlikely to be coincidental, and we are currently investigating whether they have evolved to meet a similar physiological need in differing chemical environments. Pairing ferroxidation with amine oxidation may be a neuroprotective means of preventing the oxidation of catecholamines by Fe3+ into toxic products, particularly at sites of high catecholamine levels such as the synapse. Amine oxidase activity could also facilitate the loading of Fe3+ onto iron transporting proteins (e.g. transferrin) by preventing Fe3+ reduction by local catecholamines or other bioamines.
The modulation of catecholamine levels in the brain is an important end-effect for several major classes of psychotropic drugs. The discovery that APP has an adjustable activity that influences catecholamine levels at these sites has important implications for clinical pharmacology.
Iron homeostasis in neurodegenerative disease.
Iron is essential for the normal function of the body as its ability to freely receive and donate electrons is critical for many metabolic processes including oxidative phosphorylation, nitric oxide metabolism, oxygen transport and neurotransmitter production. A deficiency in iron can lead to metabolic stress on these processes. But when this metal is at an increased presence and not correctly guarded it can be converted to a potentially harmful product that leads to an increased susceptibility to oxidative stress. The balance between disposing of and retaining iron is fundamental for keeping a healthy cell. While much work over the years has been done to investigate the homeostasis of iron throughout the body, very little is known as to how iron is regulated within the different cell types of the brain. In particular how each cell type is able to independently regulate this metal but also assist neighbouring cells of a different type with their transport of iron. The ageing brain is particularly vulnerable to cellular iron dysregulation as are patients with a broad range of brain disorders, including Alzheimer’s and Parkinson's disease. amd a better understanding is required as to how this occurs. While our research focuses on alterations in the expression and activity of ferroxidases, the group also investigates the role all iron regulatory proteins play in the brain's cellular import, storage and export under conditions that simulate neurodegenerative disease and their involvement in the oxidative damage commonly observed in neurodegenerative disease.
Investigating metal related disease-modifying treatments for relevant neurological disorders.
Metal dyshomeostasis and oxidative damage are common features of neurodegenerative diseases such as PD, Alzheimer's disease and Huntington's disease. It was originally believed that general removal of metals from tissue by 'chelation' was the best course of action in these diseases. However, as was explained earlier, metal homeostasis in the brain is paramount for a healthy cell and deficiency in cellular metals can often be just as detrimental as accumulation. It is for this reason that recent extensive work on the neuroprotective mechanism of metal attenuating compounds now suggests a more subtle mechanism of action whereby they restore brain biometals to their correct anatomical compartments via an ability to perform as transition metal ionophores or 'chaperones'. A central aim of our research has been to identify metal attenuating compounds that can mitigate ongoing neuronal loss after the cell death cascade has already commenced. However, while these compounds were effective in preventing neuronal injury when administered before neurodegeneration, it was significantly less effective when administered after initiation of the lesion. We are therefore currently heavily involved in searching for more effective molecules that are suitably neuroprotective even when administered after disease onset.
Institute of Molecular and Cellular Biology
University of Leeds
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